In recent years, with the increase of the elderly people's ratio among social population, elderly people's dementia has become a social problem. Dementia is roughly classified into Alzheimer type dementia, cerebrovascular dementia, and dementia with Lewy bodies, and especially the Alzheimer type dementia, of which number of patients is large, and for which countermeasure is difficult, poses a problem.
Neurofibrillary tangles in the cerebrum and increase in senile plaques are considered to be the causes of Alzheimer type dementia (Jack C R et al. (2010) Progress of Alzheimer disease, Lancet Neurol., 9, 119, 2010).
In the brain, the limbic system bears an important role for memory, and especially the hippocampus and the mammillary body are important organs that govern memory.
Although acetylcholine esterase inhibitors such as donepezil, galanthamine, and rivastigmine, and memantine, which is an NMDA receptor antagonist, are clinically used so far for improving symptoms of Alzheimer type dementia, sufficient curative effect has not been obtained yet.
Other than those mentioned above, as clinical trials for Alzheimer type dementia, there have been conducted clinical trials of AN1792 (Elan Pharmaceuticals), which is an amyloid vaccine, atorvastatin (Pfizer), and simvastatin (Merck), which are HMG-CoA reductase inhibitors, Dimebon (Pfizer), which is an antihistamine, tarenflurbil (Myriad Genetics), which is an NSAID, phenserine (Axonyx), which is an acetylcholine esterase inhibitor, rosiglitazone (Glaxo SmithKline), which is a PPARγ agonist, tramiprosate (Neurochem), which is an amyloid β polymerization inhibitor, xaliproden (Sanofi), which is a serotonin 1A receptor agonist, bapineuzumab (Pfizer), which is an antibody directed to the N-terminus of β amyloid, solanezumab (Eli Lilly), which is a monoclonal antibody directed to a central portion of β amyloid as an epitope, semagacestat (Eli Lilly), which is an inhibitor of γ-secretase involved in the β amyloid protein synthesis, and so forth. However, all of these could not exhibit any usefulness for the Alzheimer type dementia due to problems concerning validity or side reaction.
At present, there are being developed AZD3293 (AstraZeneca, Eli Lilly), which is an inhibitor of β secretase involved in the β amyloid protein synthesis, LuAE58054 (Lundbeck, Otsuka Pharmaceutical), which is a serotonin 5-HT6 receptor antagonist, and LuAF20513 (Lundbeck, Otsuka Pharmaceutical), which is a peptide vaccine of β amyloid. However, success of these is not guaranteed at all, in view of the fact that clinical developments of almost all the medicaments for Alzheimer's disease ended in failure.
Xanthine oxidase inhibitors such as allopurinol (Journal of the American Chemical Society (1956), 78, 784-90; Journal of the Chemical Society (1958), 2973-81), oxypurinol (Bulletin des Travaux de la Societe de Pharmacie de Bordeaux (1928) 66, 8-12; Berichte der Deutschen Chemischen Gesellschaft (1911), 44, 2155-8), febuxostat (Japanese Patent Nos. 2725886, 2706037, and 3202607), and topiroxostat (Japanese Patent Nos. 3600832, 3779725, and Japanese Patent Unexamined Publication (KOKAI) No. 2005-041802) are medicaments generally considered to be useful for the therapeutic treatment of hyperuricemia. All of these substances are compounds obtained in the process of preparing xanthine derivatives.
As references describing the relation between the xanthine oxidase inhibitor and dementia, there are Japanese Patent Unexamined Publication (KOHYO) No. 2007-533751 and Japanese Patent Unexamined Publication (KOKAI) No. 2003-201255, and any other prior references have not been found.
Japanese Patent Unexamined Publication (KOHYO) No. 2007-533751 describes a method for treatment of an Alzheimer's disease patient with a reactive oxygen-generating enzyme inhibitor in claim 25, and exemplifies xanthine oxidase inhibitor as the reactive oxygen-generating enzyme inhibitor. However, this reference specifically discloses only effects of allopurinol and nitrated allopurinol on sarcomere length and systolic calcium transient, which are indices of contraction of isolated cardiac muscle cells derived from nNOS-deficient rats (Japanese Patent Unexamined Publication (KOHYO) No. 2007-533751, FIG. 1). In addition, there are described use thereof for therapeutic treatment of Alzheimer's disease together with uses for heart failure (claim 6), stable angina pectoris (claim 8), ischemic reperfusion injury (claim 10), sickle cell disease (claim 12), heart failure, skeletal muscle force reduction, and respiratory failure (claim 17), atherosclerosis (claim 20), Parkinson's disease (claim 22), diabetes-related pain of lower extremities (claim 27), ALS (claim 29), and asthma (claim 31), as if they are in the same category. Therefore, it is regarded that this reference only mentions the use for Alzheimer's disease as one of efficacies of omnipotent reactive oxygen-generating enzyme inhibitors. As descriptions concerning Alzheimer's disease, Japanese Patent Unexamined Publication (KOHYO) No. 2007-533751 describes in Working Example XI that “A 65-year old with Alzheimer's disease is begun on 300 mg/day nitrated allopurinol (16). His memory and cognitive functions are stabilized after 3 months”. However, this description does not include any description concerning specific administration frequency or specific cognitive performance improvement index. In addition, this description is a so-called predictive statement described in the present tense, and this reference neither refers to the action mechanism, nor confirms even that nitrated allopurinol has the xanthine oxidase inhibitory activity. Therefore, the efficacy of reactive oxygen-generating enzyme inhibitors cannot be enlarged over use for Alzheimer's disease.
According to Japanese Patent Unexamined Publication (KOKAI) No. 2003-201255, there were prepared nerve cells obtained by stably overexpressing both the ecdysone receptor EcR and retinoid X receptor for raising the sensitivity of the foregoing receptor in cells of the F11 cell strain, which are fusion cells of rat primarily cultured nerve cells and mouse neuroblastomas, and further transforming the cells with a plasmid that expresses an N141I mutant of presenilin 2 as the catalytic subunit of the γ-secretase, which mutant is a mutant that causes familial Alzheimer's disease upon addition of ecdysone, and death of the nerve cells caused by addition of ecdysone was examined. As a result, the nerve cell death was suppressed by (1) simultaneous addition of 100 μM of oxypurinol as a xanthine oxidase inhibitor and 100 μM of acetyl-L-aspartyl-L-glutamyl-L-valyl-L-aspart-1-al as a caspase inhibitor, (2) simultaneous addition of 100 nM of (−)-4-hydroxy-8-(3-methoxy-4-phenylsulfinylphenyl)pyrazolo[1,5-a]-1,3,5-triazine sodium salt as a xanthine oxidase inhibitor and 100 μM of acetyl-L-aspartyl-L-glutamyl-L-valyl-L-aspart-1-al as a caspase inhibitor, and (3) simultaneous addition of 100 μM of oxypurinol as a xanthine oxidase inhibitor and 300 μM of apocynin as a NADPH oxidase inhibitor, and therefore this reference proposes an agent for prophylactic and/or therapeutic treatment of Alzheimer's disease containing a xanthine oxidase inhibitor, and an NADPH oxidase inhibitor and/or a caspase inhibitor as active ingredients.
However, in Japanese Patent Unexamined Publication (KOKAI) No. 2003-201255, suppression of the nerve cell death is not observed at all with a xanthine oxidase inhibitor alone, and therefore it cannot be said that that is the effect of xanthine oxidase inhibitor alone. Further, Japanese Patent Unexamined Publication (KOKAI) No. 2003-201255 describes only results of investigations at cell level, and therefore it is completely unknown whether such an agent can prevent or improve degeneration or reduction of nerve cells in an individual of animal. Furthermore, it cannot be confirmed that such an agent can prevent degeneration of a part of the cerebrum responsible for the cognitive function, or can prevent degradation of actual cognitive function from the descriptions of Japanese Patent Unexamined Publication (KOKAI) No. 2003-201255, and therefore it is completely unknown whether a xanthine oxidase inhibitor can prevent and/or cure dementia.
Any other prior techniques referring to the relation between a xanthine oxidase inhibitor and dementia are not known. Therefore, any prior art that teaches use of a xanthine oxidase inhibitor alone for prophylactic and/or therapeutic treatment of degradation of cognitive function in dementia is not known.
International Patent Publications WO2003/42185 and WO2005/121153 disclose compounds having a xanthine oxidase inhibitory action, and teach that these compounds are useful as prophylactic or therapeutic agent for hyperuricemia and gout.